| Gene/Disease Pair: | RAF1 : Noonan syndrome |
| HGNC:9829 | MONDO_0018997 | |
| Mode of Inheritance: | Autosomal dominant inheritance (HP:0000006) |
| Expert Panel: | RASopathy EP |
| SOP: | Gene Clinical Validity Standard Operating Procedures (SOP), Version 5 |
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Genetic Evidence
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Case-Level Data
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Evidence Type | Case Information Type | Guidelines | Points | PMIDs/Notes | ||||||
| Default | Range | Max | Total | Counted | ||||||||
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Variant Evidence
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Autosomal Dominant or X-linked Disorder | Variant is de novo | 2 | 0-3 | 12 |
10
|
10 |
Zarate YA et al. 2014 Aug (PMID:23877478); Sana ME et al. 2014 Aug (PMID:24782337); Schulz S et al. 2012 Oct (PMID:22821648); Kobayashi T et al. 2010 Mar (PMID:20052757);
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| Proband with predicted or proven null variant | 1.5 | 0-2 | 10 | |||||||||
| Proband with other variant type with some evidence of gene impact | 0.5 | 0-1.5 | 7 |
3.5
|
3.5 |
Razzaque MA et al. 2007 Aug (PMID:17603482); Hopper RK et al. 2015 Apr (PMID:25706034); Cianci P et al. 2013 Jun (PMID:23613113);
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| Autosomal Recessive Disease | Two variants in trans and at least one de novo or a predicted/proven null variant | 2 | 0-3 | 12 |
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| Two variants (not predicted/proven null) with some evidence of gene impact in trans | 1 | 0-1.5 | ||||||||||
| Segregation Evidence | Evidence of segregation in one or more families | Sequencing Method | 0-3 | 3 |
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| Total LOD Score | Canditate Gene Sequencing | Exome/Genome or all genes sequenced in linkage region | ||||||||||
| 2-2.99 | 0.5 | 1 | ||||||||||
| 3-4.99 | 1 | 2 | ||||||||||
| ≥5 | 1.5 | 3 | ||||||||||
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Case-Control Data
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Case-Control Study Type | Case-Control Quality Criteria | Guidelines | Points | PMIDs/Notes | |||||||
| Points/Study | Max | Total | Counted | |||||||||
| Single Variant Analysis | 1. Variant Detection Methodology 2. Power 3. Bias and confounding 4. Statistical Significance |
0-6 | 12 |
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| Aggregate Variant Analysis | 0-6 |
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| Total Genetic Evidence Points (Maximum 12) | 12 |
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Experimental Evidence
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Evidence Category | Evidence Type | Guidelines | Points | PMIDs/Notes | |||||||
| Default | Range | Max | Total | Counted | ||||||||
| Function | Biochemical Function | 0.5 | 0 - 2 | 2 |
0
|
0.5 |
Pandit B et al. 2007 Aug (PMID:17603483);
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| Protein Interaction | 0.5 | 0 - 2 | 0.5 |
Cianci P et al. 2013 Jun (PMID:23613113);
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| Expression | 0.5 | 0 - 2 | 0 |
Razzaque MA et al. 2007 Aug (PMID:17603482);
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| Functional Alteration | Patient cells | 1 | 0 - 2 | 2 |
|
0 | ||||||
| Non-patient cells | 0.5 | 0 - 1 | 0 |
Razzaque MA et al. 2007 Aug (PMID:17603482); Kobayashi T et al. 2010 Mar (PMID:20052757);
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| Models | Non-human model organism | 2 | 0 - 4 | 4 | 1 | 1 |
Wu X et al. 2011 Mar (PMID:21339642);
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| Cell culture model | 1 | 0 - 2 | 0 |
Dhandapany PS et al. 2011 Jul (PMID:21440552);
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| Rescue | Rescue in human | 2 | 0 - 4 |
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| Rescue in non-human model organism | 2 | 0 - 4 | ||||||||||
| Rescue in cell culture model | 1 | 0 - 2 | ||||||||||
| Rescue in patient cells | 1 | 0 - 2 | ||||||||||
| Total Experimental Evidence Points (Maximum 6) | 1.5 |
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| Assertion criteria | Genetic Evidence (0-12 points) | Experimental Evidence
(0-6 points) |
Total Points
(0-18) |
Replication Over Time (Y/N) | ||
| Description | Case-level, family segregation, or case-control data that support the gene-disease association | Gene-level experimental evidence that support the gene-disease association | Sum of Genetic & Experimental
Evidence |
> 2 pubs w/ convincing evidence over time (>3 yrs) | ||
| Assigned Points | 12 | 1.5 | 13.5 | YES | ||
| CALCULATED CLASSIFICATION | LIMITED | 1-6 | ||||
| MODERATE | 7-11 | |||||
| STRONG | 12-18 | |||||
| DEFINITIVE | 12-18 AND replication over time | |||||
| Valid contradictory evidence (Y/N)*
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| CALCULATED CLASSIFICATION (DATE) |
Definitive
07/24/2018
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| EXPERT CURATION (DATE) |
Definitive
07/24/2018
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| EVIDENCE SUMMARY |
There is a definitive association between alteration of the RAF1 gene and the NS phenotype. The maximum amount of scorable genetic evidence has been published showing de novo as well as segregating variants occur in RAF1 in patients with NS (Cianci et al., 2013; Hopper, Feinstein, Manning, Benitz, & Hudgins, 2015; Kobayashi et al., 2010; Luo et al., 2012; Razzaque et al., 2007; Sana et al., 2014; Schulz, Frober, Kraus, & Schneider, 2012; Zarate et al., 2014). The RAF1 gene is also located in the Ras/MAPK pathway which is associated with the NS phenotype and variants found in NSML patients in this gene disrupt the RAS pathway function as demonstrated by mouse knock-in and rescue models (Aoki et al., 2016; Rauen, 2013; Wu et al., 2011).
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